Volumetric MRI Analysis of the Brain Pain Matrix in Fibromyalgia: Unraveling the Structural Changes and Neural Mechanisms of Chronic Pain

Volumetric MRI Analysis of the Brain Pain Matrix in Fibromyalgia: Unraveling the Structural Changes and Neural Mechanisms of Chronic Pain | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Volumetric MRI Analysis of the Brain Pain Matrix in Fibromyalgia: Unraveling the Structural Changes and Neural Mechanisms of Chronic Pain rodi pala, sultan tarlacı This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8186703/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Fibromyalgia (FM) is a chronic pain syndrome predominantly affecting women, characterized by widespread pain, sensory hypersensitivity, fatigue, and sleep disturbances. Recent evidence suggests that chronic pain in FM is closely associated with dysfunctions in the central nervous system (CNS). This study aims to identify volumetric brain changes observed in FM patients and to evaluate the relationship between these structural alterations and neural plasticity mechanisms. Methods The study included 32 female patients diagnosed with FM (aged 22–79 years; mean age: 44.72 ± 12.63) and 31 age- and sex-matched healthy controls (aged 24–56 years; mean age: 37.87 ± 8.29). There was no significant age difference between the groups (p = 0.102). High-resolution T1-weighted magnetic resonance imaging (MRI) data were analyzed using the vol2Brain module of the volBrain platform. Volumetric measurements were obtained for 135 distinct brain regions. Results Volumetric analyses revealed marked changes in the limbic system structures of FM patients. Increased volumes were observed in the thalamus, amygdala, and hippocampus, whereas the anterior and medial cingulate gyri and insular cortex exhibited decreased volumes. Additional findings included an increase in total white matter (WM) and subcortical gray matter, along with a reduction in cerebellar WM volume. Conclusion The results underscore the neurobiological basis of FM and suggest that the observed structural changes are linked to neural plasticity mechanisms within the CNS. Identifying FM-specific volumetric alterations may support the development of personalized and targeted therapeutic interventions. Anesthesiology & Pain Medicine Computational Neuroscience Neurobiology of Disease Fibromyalgia Chronic Pain Pain Matrix MRI Imaging Brain Structures Introduction Chronic pain poses a significant public health challenge due to its high prevalence and the complexities involved in clinical management. 1 Fibromyalgia syndrome (FMS) is one of the most prevalent chronic pain disorders, characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive impairments. 2 , 3 Affecting an estimated 2% to 5% of the general population, fibromyalgia (FM) predominantly occurs in women and significantly compromises both daily functioning and overall quality of life. 4 , 5 Currently, there is no universally effective treatment for FMS, and full recovery remains rare. 6 The pathogenesis of FM is still not fully understood; however, genetic, biological, and psychosocial factors are thought to play roles in this complex condition. 7 In this context, FMS is recognized as a prototypical condition among chronic pain disorders, where pain cannot be fully explained by peripheral tissue damage or identifiable nervous system lesions. 8 Recent studies suggest that central nervous system (CNS) mechanisms are crucial in the pathogenesis of chronic pain in FM. 5 These mechanisms involve central sensitization, pain persistence, 9 and maladaptive neuroplasticity associated with neurochemical dysregulation. 4 In 2017, the International Association for the Study of Pain (IASP) introduced the concept of "nociplastic pain" to complement nociceptive and neuropathic pain classifications. 10 Nociplastic pain refers to pain arising from altered nociceptive function without clear evidence of tissue damage or nervous system lesions, encompassing conditions such as FM and irritable bowel syndrome. 10 This conceptualization supports the classification of FMS as a centrally mediated pain disorder, reinforcing the clinical understanding of its pathophysiology. 11 , 12 Advancements in neuroimaging technologies have enabled direct observation of CNS regions activated during pain, 13 thus enhancing our understanding of the neurobiological underpinnings of complex pain syndromes such as FM. 14 Functional MRI (fMRI) studies have shown that FM patients process pain differently from healthy individuals. 15 Furthermore, voxel-based morphometry (VBM) studies have revealed significant structural differences in brain areas associated with the pain matrix in FM. 16–21 These include volumetric alterations in total brain volume, 21 the thalamus, 19 and the cerebellum. 20 Such changes are frequently linked to cortical plasticity processes, supporting the notion that the brain undergoes structural adaptation in response to chronic pain. 22 Persistent CNS stimulation from chronic pain may lead to adaptive or maladaptive remodeling in relevant neural networks over time. 23 However, some studies indicate that these morphometric alterations may be reversible when pain levels decrease, suggesting they reflect dynamic and potentially modifiable neural processes rather than permanent damage. 24,25 Given this context, detailed investigations into FM-specific structural brain patterns are needed to better understand the plasticity dynamics involved. The present study aims to identify volumetric brain changes observed in FM patients and to assess whether these alterations offer insights into neural plasticity mechanisms underlying chronic pain. High-resolution T1-weighted brain MRI data from female FM patients were compared to those from age- and sex-matched healthy female controls (HC). Volumetric analyses were conducted using the vol2Brain module of the volBrain platform. This AI-powered, user-friendly, and non-invasive tool 26 provides volumetric data for 135 different brain regions, including cortical and subcortical structures, white matter (WM), brainstem, cerebellum, and cerebrospinal fluid (CSF). 27 These comprehensive data offer valuable insights into the neurobiological mechanisms of FM and the potential clinical implications of structural brain alterations. Understanding the neurobiological basis of FM is essential not only for improving diagnostic accuracy but also for guiding personalized treatment approaches. Accordingly, this study seeks to uncover FM-specific volumetric changes that may pave the way for individualized and targeted therapeutic interventions. It is hypothesized that volumetric analyses will reveal meaningful and specific brain volume differences in FM patients. MATERIALS AND METHOD Participants This study compared brain MRI data from 32 female patients diagnosed with FM and 31 female control group. The data were retrospectively obtained from the archive records of NPIstanbul Brain Hospital. All data were anonymized to protect participants' personal identity. The research protocol was approved by the Üsküdar University Ethics Committee under the protocol number 61351342/JAN 2024 − 101. Participants in the FM group were selected based on the 1990 American College of Rheumatology (ACR) classification criteria for fibromyalgia. Diagnoses were made by a neurologist based on the presence of tenderness upon palpation in at least 11 of 18 anatomical regions, with tenderness distributed across both the axial skeleton and diagonally opposite quadrants of the body. 28 The control group consisted of healthy women aged between 24 and 56 years. Inclusion criteria for both groups were: (1) being female, and (2) being 18 years of age or older. Exclusion criteria included: (1) being under 18 or over 80 years of age, and (2) being male. These criteria were implemented to minimize potential sex-related bias in structural MRI results. MRI Acquisition Parameters Brain MRI scans were performed at NPIstanbul Brain Hospital using a 1.5 Tesla Philips Achieva scanner (Philips Medical Systems, Best, Netherlands) equipped with an 8-channel SENSE head coil. High-resolution T1-weighted images were acquired using the 3D magnetization-prepared rapid gradient-echo (MPRAGE) technique. Imaging parameters were as follows: acquisition matrix: 256 x 256 x 140; repetition time (TR): 2.8 s; echo time (TE): 4.0 s; flip angle: 8°; field of view (FOV): 240 mm; coronal slices: 135; voxel size: 0.937 × 0.937 × 1.2 mm resolution. VolBrain Analysis In this study, automatic and quantitative analyses of MR data were conducted using the vol2Brain 1.0 pipeline. volBrain is an online platform that performs volumetric analysis of brain structures based on high-resolution T1-weighted 3D MPRAGE MRI images. 26 Historically, brain volume segmentation and quantification via MRI was time-consuming and required manual procedures informed by expert neuroanatomical knowledge. However, the volBrain platform developed by Manjón and Coupé enables automatic volumetric and cortical thickness analyses. 27 In a comparative study, a high correlation was found between manual measurements and values obtained through volBrain analysis, confirming the tool’s validity.²⁹ volBrain operates without the need for specialized technical training. After registering on the system, users upload their T1-weighted brain MR images in NIfTI format. The images are then processed via distributed computing across multiple supercomputers on the volBrain web server. 26 The volBrain pipeline incorporates a series of preprocessing and segmentation steps to enhance input image quality and accurately distinguish between different brain structures and tissues. These steps include spatially adaptive non-local denoising, rough bias field correction, affine registration to MNI space, fine-level SPM-based bias correction, intensity normalization, non-local intracranial cavity extraction (NICE), tissue classification, non-local hemisphere segmentation (NABS), and non-local subcortical structure segmentation. 26 The system analyzes 135 brain regions—including intracranial cavity (ICV), white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), cerebrum, cerebellum, brainstem, and subcortical gray matter (sGM)—while accounting for demographic factors such as age and sex. 27 Tissue volumes are reported in absolute values (cm³) and as percentage ratios of each structure's volume relative to the intracranial volume. Additionally, an asymmetry index is calculated based on the difference between right and left hemisphere volumes relative to their mean, and this is also expressed as a percentage. 27 In the present study, percentage values obtained from volBrain were used for statistical analysis. Statistical Analysis Statistical analyses were conducted using SPSS version 27 (IBM Corporation, Armonk, NY, USA) and JASP version 0.9. Levene’s F-test was initially applied to assess the homogeneity of variance between groups. When variance was found to be homogeneous, independent samples t-tests were used to examine whether brain volume differences between the FM and HC groups were statistically significant. Given the large number of brain regions analyzed (a total of 135), particular attention was paid to volumetric changes observed in specific areas of the pain matrix and related structures. A 95% confidence interval was adopted for all tests, and a p -value less than 0.05 was considered statistically significant. Considering the large number of brain regions analyzed (n = 135), and to address the inflation of Type I error due to multiple comparisons, the False Discovery Rate (FDR) correction method proposed by Benjamini and Hochberg (1995) was applied to all p -values. 30 This method is widely used in neuroimaging studies involving multiple parallel tests, as it controls the expected proportion of false positives among statistically significant findings. 31 , 32 The application of the Benjamini-Hochberg FDR procedure to the comprehensive set of independent sample t-tests effectively distinguished robust findings from those that may have reached significance by chance. This refinement is a crucial step as it allows for more reliable interpretation of the results, highlights only the most robust effects, and helps prevent the overstatement of findings. Results Demographic Characteristics The study sample consisted of 32 female FM patients aged 22–79 years and 31 female HC participants aged 24–56 years. The mean age of the FM group was 44.72 ± 12.63 years, while the HC group had a mean age of 37.87 ± 8.29 years. No statistically significant difference in age was observed between the two groups ( p = 0.102). Volumetric Analyses Group comparisons revealed significant volumetric differences in brain structures between FM patients and HC participants (see Table 1 ). FM patients exhibited significantly greater total white matter (WM) volume (473.086 ± 47.035 cm³) compared to HC (380.202 ± 92.292 cm³, p = 0.001). Similarly, subcortical gray matter (sGM) volume was significantly increased in the FM group (40.988 ± 2.983 cm³) compared to HC (34.043 ± 6.922 cm³, p = 0.001). Additionally, the total limbic system volume (38.599 ± 3.628 cm³), right limbic volume (19.032 ± 2.182 cm³), and left limbic volume (19.568 ± 1.626 cm³) were significantly lower in FM patients than in HC ( p < 0.05). Specific brain regions in FM patients also showed significant volume increases. The right amygdala volume was significantly larger in FM (0.971 ± 0.078 cm³) compared to HC (0.870 ± 0.130 cm³, p = 0.001). Total amygdala volume (1.920 ± 0.171 cm³ vs. 1.762 ± 0.240 cm³, p = 0.004), total hippocampal volume (8.148 ± 0.620 cm³ vs. 7.337 ± 1.073 cm³, p = 0.001), and total thalamic volume (11.879 ± 1.155 cm³ vs. 7.574 ± 3.776 cm³, p = 0.001) were also significantly greater in the FM group. Conversely, several brain regions exhibited significant volumetric reductions in the FM group. Cerebellar WM volume was lower in FM patients (30.887 ± 3.350 cm³) compared to HC (36.221 ± 7.288 cm³, p = 0.001). Total insular cortex volume was significantly reduced in FM (27.302 ± 2.909 cm³) compared to HC (29.167 ± 3.954 cm³, p = 0.037), along with the left insula volume (14.015 ± 1.468 cm³ vs. 15.124 ± 2.116 cm³, p = 0.018), and total anterior insula volume (7.666 ± 0.644 cm³ vs. 8.391 ± 0.935 cm³, p = 0.001). Additionally, both right anterior insula volume (3.816 ± 0.346 cm³ vs. 4.229 ± 0.522 cm³, p = 0.001) and left anterior insula volume (3.850 ± 0.339 cm³ vs. 4.162 ± 0.470 cm³, p = 0.004) were significantly smaller in FM. Among the key components of the limbic system, total anterior cingulate gyrus (ACG) volume was significantly reduced in FM (10.319 ± 1.370 cm³) compared to HC (11.741 ± 1.917 cm³, p = 0.001), as were right ACG (4.942 ± 0.931 cm³ vs. 5.548 ± 0.908 cm³, p = 0.011) and left ACG (5.377 ± 0.606 cm³ vs. 6.193 ± 1.161 cm³, p = 0.001) volumes. Similarly, total medial cingulate gyrus (MCG) volume (9.736 ± 1.051 cm³ vs. 12.076 ± 2.016 cm³, p = 0.001), right MCG (4.831 ± 0.668 cm³ vs. 5.863 ± 0.940 cm³, p = 0.001), and left MCG (4.904 ± 0.548 cm³ vs. 6.214 ± 1.147 cm³, p = 0.001) were significantly lower in FM patients. Significant volumetric differences were also found in the nucleus accumbens (NA), with FM patients showing reduced total NA volume (0.633 ± 0.129 cm³) compared to HC (0.534 ± 0.139 cm³, p = 0.005). Both right ( p = 0.017) and left ( p = 0.002) NA volumes were also significantly lower in the FM group. Table 1 Comparison of Brain Regions Showing Significant Volume Differences (cm³) Between FM and Control Groups Volume FM (n = 32) HC (n = 31) p -value Total WM 473.086 ± 47.035 380.202 ± 92.292 0.001 WM (R) 237.282 ± 24.071 195.771 ± 44.239 0.001 WM (L) 235.804 ± 23.026 184.431 ± 48.369 0.001 CSF 167.765 ± 36.457 221.877 ± 62.682 0.001 Subkortikal GM 40.988 ± 2.983 34.043 ± 6.922 0.001 Cerebral Hemisphere (R) 508.436 ± 42.292 459.768 ± 67.908 0.001 Cerebral Hemisphere (L) 507.308 ± 41.261 447.547 ± 72.024 0.001 Serebellum WM 30.887 ± 3.350 36.221 ± 7.288 0.001 Insular Cortex (Total) 27.302 ± 2.909 29.167 ± 3.954 0.037 Insular Cortex (L) 14.015 ± 1.468 15.124 ± 2.116 0.018 Anterior Insula (Total) 7.666 ± 0.644 8.391 ± 0.935 0.001 Anterior Insula (R) 3.816 ± 0.346 4.229 ± 0.522 0.001 Anterior Insula (L) 3.850 ± 0.339 4.162 ± 0.470 0.004 Limbic System (Total) 38.599 ± 3.628 41.979 ± 4.798 0.002 Limbic System (R) 19.032 ± 2.182 20.275 ± 2.160 0.027 Limbic System (L) 19.568 ± 1.626 21.705 ± 2.761 0.001 Amygdala (Total) 1.920 ± 0.171 1.762 ± 0.240 0.004 Amygdala (R) 0.971 ± 0.078 0.870 ± 0.130 0.001 Nucleus Accumbens (Total) 0.633 ± 0.129 0.534 ± 0.139 0.005 Nucleus Accumbens (R) 0.305 ± 0.064 0.263 ± 0.073 0.017 Nucleus Accumbens (L) 0.328 ± 0.068 0.271 ± 0.072 0.002 Basal Forebrain (Total) 0.699 ± 0.106 0.593 ± 0.131 0.001 Basal Forebrain (R) 0.363 ± 0.056 0.294 ± 0.075 0.001 Basal Forebrain (L) 0.336 ± 0.059 0.298 ± 0.062 0.018 Anterior Cingulate Gyrus (Total) 10.319 ± 1.370 11.741 ± 1.917 0.001 Anterior Cingulate Gyrus (R) 4.942 ± 0.931 5.548 ± 0.908 0.011 Anterior Cingulate Gyrus (L) 5.377 ± 0.606 6.193 ± 1.161 0.001 Medial Cingulate Gyrus (Total) 9.736 ± 1.051 12.076 ± 2.016 0.001 Medial Cingulate Gyrus (R) 4.831 ± 0.668 5.863 ± 0.940 0.001 Medial Cingulate Gyrus (L) 4.904 ± 0.548 6.214 ± 1.147 0.001 Hippocampus (Total) 8.148 ± 0.620 7.337 ± 1.073 0.001 Hippocampus (R) 4.107 ± 0.294 3.639 ± 0.611 0.001 Hippocampus (L) 4.041 ± 0.341 3.698 ± 0.511 0.003 Thalamus (Total) 11.879 ± 1.155 7.574 ± 3.776 0.001 Thalamus (R) 5.892 ± 0.542 3.714 ± 1.906 0.001 Thalamus (L) 5.987 ± 0.628 3.860 ± 1.878 0.001 Angular Gyrus (R) 9.847 ± 1.179 10.966 ± 2.005 0.009 Supramarginal Gyrus (R) 7.771 ± 1.082 8.442 ± 1.123 0.019 Postcentral Gyrus (Total) 18.320 ± 2.293 20.419 ± 2.549 0.001 Postcentral Gyrus (R) 9.099 ± 1.232 10.023 ± 1.351 0.006 Postcentral Gyrus (L) 9.221 ± 1.231 10.396 ± 1.296 0.001 WM: White Matter, GM: Gray Matter, CSF: Cerebrospinal Fluid, R: Right, L: Left FDR-Corrected Brain Volume Analysis Results Following FDR correction, a substantial number of brain regions retained statistical significance, indicating robust and reliable group differences. The most prominent findings were observed in subcortical and white matter structures. In particular, the thalamus (total, right, and left volumes), total white matter in both hemispheres, and cerebral white matter exhibited highly significant differences ( p < .001). Core components of the limbic system—including the amygdala (especially the right side), bilateral nucleus accumbens, basal forebrain also remained significant after FDR adjustment. Additionally, several cortical regions, notably the anterior and medial cingulate cortex, postcentral gyrus, frontal pole, medial segments of the superior frontal gyrus, and the supplementary motor cortex, survived correction. The consistency of these findings across related structures (e.g., bilateral thalamus and multiple frontal regions) further strengthens the overall results. Conversely, several variables that initially reached significance at the conventional p < .05 threshold did not survive FDR correction. These less robust or potentially false-positive findings include the right angular gyrus, supramarginal gyrus, left inferior frontal gyrus (pars triangularis), and the left medial frontal cortex. The loss of significance in these specific cortical areas suggests that, while subtle differences may exist, they are not strong enough to be distinguished from noise once false discovery rates are controlled. The implementation of the FDR correction thus yielded a clear and focused pattern of brain volume differences based on rigorous multiple comparison adjustments. This approach confirms that the volumetric differences observed between the FM and HC groups are statistically meaningful and reliable, rather than attributable to random variation. Tablo 2. FDR-Adjusted Brain Volume Comparisons Between FM and HC Groups Region df t P -value(FDR) Direction WM (Total) 45.48 4.69 .001 ↑ FM > HC Subcortical GM 40.50 5.14 .001 ↑ FM > HC Thalamus (Total) 35.41 6.08 .001 ↑ FM > HC Thalamus (R) 34.67 6.13 .001 ↑ FM > HC Thalamus (L) 36.43 5.99 .001 ↑ FM > HC Cerebrum WM (Total) 44.28 5.01 .001 ↑ FM > HC Cerebrum WM (R) 46.01 4.61 .001 ↑ FM > HC Cerebrum WM (L) 42.63 5.35 .001 ↑ FM > HC Limbic System (Total) 61.00 -3.16 .008 ↓ FM HC Amygdala (R) 48.98 3.72 .003 ↑ FM > HC Nucleus Accumbens (Total) 61.00 2.93 .014 ↑ FM > HC Nucleus Accumbens (R) 61.00 2.44 .039 ↑ FM > HC Nucleus Accumbens (L) 61.00 3.24 .007 ↑ FM > HC Basal Forebrain (Total) 61.00 3.54 .004 ↑ FM > HC Basal Forebrain (R) 61.00 4.15 .001 ↑ FM > HC Anterior Cingulate Gyrus total 54.20 -3.38 .005 ↓ FM < HC Anterior Cingulate Gyrus (R) 61.00 -2.61 .028 ↓ FM < HC Anterior Cingulate Gyrus (L) 44.87 -3.48 .005 ↓ FM < HC Medial Cingulate Gyrus total 44.85 -5.75 .001 ↓ FM < HC Medial Cingulate Gyrus (R) 54.00 -5.01 .001 ↓ FM < HC Medial Cingulate Gyrus (L) 42.70 -5.75 .001 ↓ FM < HC Postcentral Gyrus total 61.00 -3.44 .005 ↓ FM < HC Postcentral Gyrus (R) 61.00 -2.84 .018 ↓ FM < HC Postcentral Gyrus (L) 61.00 -3.69 .003 ↓ FM HC Sup. Frontal Gyrus medial segment (Total) 49.75 4.15 .001 ↑ FM > HC Sup. Frontal Gyrus medial segment (R) 45.61 4.95 .001 ↑ FM > HC Sup. Frontal Gyrus medial segment (L) 61.00 2.77 .020 ↑ FM > HC Supplementary Motor Cortex (Total) 40.97 3.86 .002 ↑ FM > HC Angular Gyrus (R) 48.22 -2.69 .025 ↓ FM < HC Supramarginal Gyrus (R) 61.00 -2.41 .041 ↓ FM HC Medial Frontal Cortex (L) 53.19 2.77 .021 ↑ FM > HC WM: White Matter, GM: Gray Matter, R: Right, L: Left; ↑ FM > HC = Increased volume in FM group compared to controls ; ↓ FM < HC = Decreased volume in FM group compared to controls; * = Survived FDR correction (significant) Discussion The primary objective of the present study was to detect volumetric changes in brain structures associated with FM using artificial intelligence-assisted MRI analysis, thereby contributing to a better understanding of the neural signature patterns of FM and chronic pain. Recent investigations provide increasing evidence that chronic pain in FM leads to structural, 33 functional 34 , 35 and neurochemical changes in brain architecture. 36 , 37 In this context, our study demonstrates striking volumetric-brain alteration patterns in FM compared with HC. Initial analyses revealed increases in total WM and sGM volumes in FM. Although volumetric studies have predominantly focused on GM, previous FM research likewise points to structural abnormalities in WM. 38,39 In a systematic review, findings from 10 DTI studies involving a total of 215 FM patients were evaluated, revealing widespread structural disruption in WM organization, including in regions such as the thalamus, frontal cortex, and corpus callosum.³⁹ Similarly, a volumetric and DTI-based study 40 found increased FA values in the superior frontal gyrus and ACG, which were significantly associated with pain and fatigue severity. The positive correlation of WM changes in FM with symptom severity may reflect maladaptive neuroplastic processes within the CNS that contribute to symptom exacerbation rather than protection. 41 Hemispheric analyses revealed significant reductions in basal forebrain volume in both right and left hemispheres, with the reduction in the right hemisphere ( p = 0.001) being more pronounced than the left ( p = 0.018). Literature indicates that the right hemisphere is more involved in alertness, broad attentional processes and processing of external stimuli, whereas the left hemisphere predominates in language and goal-directed attention. 42 The more marked right-hemisphere reduction may represent a neuroanatomical mechanism underlying attentional deficits and heightened sensitivity to external stimuli (hypervigilance) in FM. In addition to these global changes, we focused on specific brain regions impacted by volumetric alterations. The FM group exhibited a statistically significant decrease in cerebellar WM volume. Cerebellar changes in FM have also been reported in previous studies. 2 , 16 , 43 , 44 Although the cerebellum has long been considered a secondary structure in pain research, current literature indicates that it plays an active role in the pain-processing network. 16 , 44 Because of its connections to the cerebral cortex, brainstem and limbic system, the cerebellum contributes to both sensory and affective components of pain. 45 It has been further demonstrated that the cerebellum receives nociceptive inputs directly, can be activated by painful stimuli, and plays both pronociceptive and antinociceptive roles, as well as a role in coordinating pain-related motor responses and behavioural adaptations.⁴⁵ In a study examining the relationship between cerebellar structural changes and clinical symptomatology in FM, significant reductions in myelination levels were detected in left cerebellar lobules VI and VIII, and these changes were shown to correlate with anxiety levels. 44 The structural cerebellar alterations detected in FM may thus be directly related to clinical symptomatology. Given the cerebellum’s involvement in both pain modulation and cognitive function, 46 these structural changes suggest that FM patients may face difficulties in managing the cognitive and emotional dimensions of chronic pain. Structural changes in the limbic system were examined in detail. We found a significant reduction in total limbic system volume in FM, consistent with previous neuroimaging data. 47 The limbic system—comprising the amygdala, hippocampus, thalamus and ACG—is central to pain perception, emotional regulation, memory, interoception and autonomic responses. 48 , 49 Volume losses in this system may underlie the increased pain sensitivity and impaired stress regulation frequently reported in FM. Region-specific analyses revealed significant reductions in ACG and MCG volumes in FM. These regions are key to cognitive appraisal of pain and regulation of emotional responses. 50 , 51 These findings indicate impaired cognitive–affective regulation of pain and disrupted functional integrity at the limbic system level. Another key finding involved the thalamus: consistent with earlier research, 16,52 we observed increased total thalamic volume in FM. The thalamus serves as a central relay for nociceptive signals to the cortex. 53 Dysfunctional thalamic signalling in FM has been associated with disturbed transmission of nociceptive signals. 54 This impaired transmission may lower pain thresholds and contribute to central sensitization in FM. 55 The structural changes observed in the thalamus may play a role in mechanisms of brain–pain transition from localized pain to widespread allodynia in chronic pain conditions. In group comparisons, the amygdala—a further component of the limbic system—was found to have larger volume in FM. The amygdala plays a prominent role in processing fear-related emotions and emotionally associated memory. 56 Previous studies have indicated that the amygdala is activated by pain-related fear and plays a central role not only in sensory pain processing but also in associated emotional and motivational processes. 43 , 57 , 58 , 59 The increase in amygdala volume in FM supports the notion that amygdala plasticity plays a key role in the affective component of chronic pain. Our analyses also revealed hemispheric lateralization of amygdala changes in FM; consistent with previous findings, we found a particularly marked volume increase in the right amygdala. 60 , 61 Prior work suggests that right-amygdala enlargement is associated with threat perception, fear responses and rapid emotional reactions, 62 while left-amygdala changes are more linked to complex emotional evaluation, cognitive control and verbal expression of emotions. 61 , 63 The comparatively limited volume increase in the left amygdala may indicate differing hemispheric involvement. This lateralization may be an important finding for understanding individual differences in pain perception and emotional responses in FM. While prominent right-amygdala changes may explain FM’s effects on emotional responses and pain-related threat perception, changes in the left amygdala may represent neural substrates of broader cognitive and emotional dysregulation. Our analyses also showed increased hippocampal volume in FM. The hippocampus, particularly the DG, plays a crucial role in memory formation and processing, including pain-related memory. 64 Chronic pain has been shown to impair hippocampus-dependent cognitive functions and lead to memory deficits. 65 , 66 Neuroplastic changes in the hippocampus observed in FM may contribute to the formation of persistent pain memories, thus affecting emotional responses and cognitive appraisal of pain. 67 This suggests that in FM, pain may transform into a continuous recall process and contribute to intensification of pain perception via a possible neurobiological mechanism. We found significant reductions in volumes of the insular cortex (IK) and anterior insula (AIns) in FM—regions critical for pain perception, interoceptive awareness and emotional regulation. 68 The structural changes observed may disrupt the hypothalamic–pituitary–adrenal (HPA) axis regulation—an important controller of stress responses. 69 While the HPA axis normally functions adaptively under acute stress, in chronic pain conditions such as FM it may become dysfunctional, contributing to persistent stress load via inadequate or irregular cortisol responses. 70 HPA axis dysfunction is considered a possible pathway that adds to chronic stress load and insufficient cortisol responses, 71 thereby intensifying symptoms in chronic pain disorders like FM. ndeed, limbic self neuromodulation interventions targeting limbic anomalies in fibromyalgia may reduce symptom severity and overall disease burden, as shown in recent studies. 25 Additionally, volumetric analyses revealed significant reductions in NA total volume and its hemispheric subregions in FM. The NA plays a key role in reward processing, motivation, emotional regulation and pain modulation. 72 Disruption of NA-related reward mechanisms is frequently linked to anhedonia, motivation loss and emotional stress. 73 , 74 In this context, the volume loss in the NA in FM may reflect not only the physical pain component but also the psychological and emotional burden of the condition. The more pronounced loss in the left NA ( p = 0.002 vs. p = 0.017 for right) may be relevant since the left NA has been found to play a more active role in reward expectancy, emotional evaluation and processing of social-hedonic stimuli, 75 whereas the right NA is more closely associated with reward sensitivity and motivational functions. 76 The lateralization effect seen in the left NA might thus provide a neuroanatomical basis for symptoms such as anhedonia, emotional blunting and motivational loss common in FM. The findings support the view that FM is a complex, centrally mediated pain syndrome with a distinct neural-signature pattern in the CNS, offering a specific neurobiological profile and important insight into the central pathophysiology of the condition. Limitations This study's findings are constrained by a relatively small sample size, limiting generalizability. Furthermore, the cross-sectional design prevents the assessment of longitudinal changes in FM. Future research should employ larger samples and longitudinal methods to address these limitations. Conclusion This study revealed specific volumetric alterations in the central nervous system of FM patients. Structural differences in the limbic system, thalamus, hippocampus, amygdala, and insular cortex reflect neuroplastic processes affecting the sensory, emotional, and cognitive components of pain. Increased WM volumes and reductions in reward-related structures further support the conceptualization of FM as a centrally mediated, complex pain disorder. The use of AI-assisted platforms such as volBrain offers an effective, non-invasive approach to elucidating the neurobiological underpinnings of FM. Identifying these structural signatures may enhance diagnostic accuracy and support the development of personalized and targeted therapeutic strategies. Ultimately, this study emphasizes the significance of neuroimaging-based approaches in elucidating FM's underlying mechanisms and the need for neurobiologically informed, integrative pain management. Declarations Consent Statement: This retrospective study was conducted using anonymized MRI data retrieved from the hospital archive of fibromyalgia patients. The study received approval from the Üsküdar University Ethics Committee under protocol number 61351342/JAN 2024-101. The requirement for individual patient consent was waived due to the retrospective and anonymized nature of the data. Use of AI-Assisted Tools AI-assisted tools were used in the preparation of this manuscript. Specifically, SciSpace was used to identify and filter relevant academic studies, and ChatGPT (OpenAI) was used to support the clarity, academic tone, and narrative flow of the text. The authors reviewed and verified all generated content and take full responsibility for the final manuscript. Acknowledgments We thank Aslınur Çakmak for her significant contributions to the technical aspects of the study, as well as Dr. Necati Alp Tabak and Sedat Aydın for their support in providing MRI data for fibromyalgia patients. Data Availability Statement The MRI data analyzed during this study were retrospectively obtained from the archive of NPIstanbul Brain Hospital. All data were fully anonymized prior to analysis. 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Pain 158(Suppl 1):S43–S49 Elman I, Borsook D, Volkow ND (2013) Pain and suicidality: insights from reward and addiction neuroscience. Prog Neurobiol 109:1–27 Rademacher L, Salama A, Gründer G, Spreckelmeyer KN (2014) Differential patterns of nucleus accumbens activation during anticipation of monetary and social reward in young and older adults. Soc Cogn Affect Neurosci 9(6):825–831. 10.1093/scan/nst047 Xu Y, Lin Y, Yu M, Zhou K (2024) The nucleus accumbens in reward and aversion processing: insights and implications. Front Behav Neurosci 18. 10.3389/fnbeh.2024.1420028 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Pain\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic pain poses a significant public health challenge due to its high prevalence and the complexities involved in clinical management.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Fibromyalgia syndrome (FMS) is one of the most prevalent chronic pain disorders, characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive impairments.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Affecting an estimated 2% to 5% of the general population, fibromyalgia (FM) predominantly occurs in women and significantly compromises both daily functioning and overall quality of life.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Currently, there is no universally effective treatment for FMS, and full recovery remains rare.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The pathogenesis of FM is still not fully understood; however, genetic, biological, and psychosocial factors are thought to play roles in this complex condition.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e In this context, FMS is recognized as a prototypical condition among chronic pain disorders, where pain cannot be fully explained by peripheral tissue damage or identifiable nervous system lesions.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eRecent studies suggest that central nervous system (CNS) mechanisms are crucial in the pathogenesis of chronic pain in FM.\u003csup\u003e5\u003c/sup\u003e These mechanisms involve central sensitization, pain persistence,\u003csup\u003e9\u003c/sup\u003e and maladaptive neuroplasticity associated with neurochemical dysregulation.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e In 2017, the International Association for the Study of Pain (IASP) introduced the concept of \"nociplastic pain\" to complement nociceptive and neuropathic pain classifications.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Nociplastic pain refers to pain arising from altered nociceptive function without clear evidence of tissue damage or nervous system lesions, encompassing conditions such as FM and irritable bowel syndrome.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e This conceptualization supports the classification of FMS as a centrally mediated pain disorder, reinforcing the clinical understanding of its pathophysiology.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Advancements in neuroimaging technologies have enabled direct observation of CNS regions activated during pain,\u003csup\u003e13\u003c/sup\u003e thus enhancing our understanding of the neurobiological underpinnings of complex pain syndromes such as FM.\u003csup\u003e14\u003c/sup\u003e Functional MRI (fMRI) studies have shown that FM patients process pain differently from healthy individuals.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Furthermore, voxel-based morphometry (VBM) studies have revealed significant structural differences in brain areas associated with the pain matrix in FM. \u003csup\u003e16\u0026ndash;21\u003c/sup\u003e These include volumetric alterations in total brain volume,\u003csup\u003e21\u003c/sup\u003e the thalamus,\u003csup\u003e19\u003c/sup\u003e and the cerebellum.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Such changes are frequently linked to cortical plasticity processes, supporting the notion that the brain undergoes structural adaptation in response to chronic pain. \u003csup\u003e22\u003c/sup\u003e Persistent CNS stimulation from chronic pain may lead to adaptive or maladaptive remodeling in relevant neural networks over time.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e However, some studies indicate that these morphometric alterations may be reversible when pain levels decrease, suggesting they reflect dynamic and potentially modifiable neural processes rather than permanent damage. \u003csup\u003e24,25\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eGiven this context, detailed investigations into FM-specific structural brain patterns are needed to better understand the plasticity dynamics involved. The present study aims to identify volumetric brain changes observed in FM patients and to assess whether these alterations offer insights into neural plasticity mechanisms underlying chronic pain. High-resolution T1-weighted brain MRI data from female FM patients were compared to those from age- and sex-matched healthy female controls (HC). Volumetric analyses were conducted using the vol2Brain module of the volBrain platform. This AI-powered, user-friendly, and non-invasive tool\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e provides volumetric data for 135 different brain regions, including cortical and subcortical structures, white matter (WM), brainstem, cerebellum, and cerebrospinal fluid (CSF).\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e These comprehensive data offer valuable insights into the neurobiological mechanisms of FM and the potential clinical implications of structural brain alterations.\u003c/p\u003e\u003cp\u003eUnderstanding the neurobiological basis of FM is essential not only for improving diagnostic accuracy but also for guiding personalized treatment approaches. Accordingly, this study seeks to uncover FM-specific volumetric changes that may pave the way for individualized and targeted therapeutic interventions. It is hypothesized that volumetric analyses will reveal meaningful and specific brain volume differences in FM patients.\u003c/p\u003e"},{"header":"MATERIALS AND METHOD","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eThis study compared brain MRI data from 32 female patients diagnosed with FM and 31 female control group. The data were retrospectively obtained from the archive records of NPIstanbul Brain Hospital. All data were anonymized to protect participants' personal identity. The research protocol was approved by the \u0026Uuml;sk\u0026uuml;dar University Ethics Committee under the protocol number 61351342/JAN 2024\u0026thinsp;\u0026minus;\u0026thinsp;101.\u003c/p\u003e\u003cp\u003eParticipants in the FM group were selected based on the 1990 American College of Rheumatology (ACR) classification criteria for fibromyalgia. Diagnoses were made by a neurologist based on the presence of tenderness upon palpation in at least 11 of 18 anatomical regions, with tenderness distributed across both the axial skeleton and diagonally opposite quadrants of the body.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e The control group consisted of healthy women aged between 24 and 56 years.\u003c/p\u003e\u003cp\u003eInclusion criteria for both groups were: (1) being female, and (2) being 18 years of age or older. Exclusion criteria included: (1) being under 18 or over 80 years of age, and (2) being male. These criteria were implemented to minimize potential sex-related bias in structural MRI results.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMRI Acquisition Parameters\u003c/h3\u003e\n\u003cp\u003eBrain MRI scans were performed at NPIstanbul Brain Hospital using a 1.5 Tesla Philips Achieva scanner (Philips Medical Systems, Best, Netherlands) equipped with an 8-channel SENSE head coil. High-resolution T1-weighted images were acquired using the 3D magnetization-prepared rapid gradient-echo (MPRAGE) technique. Imaging parameters were as follows: acquisition matrix: 256 x 256 x 140; repetition time (TR): 2.8 s; echo time (TE): 4.0 s; flip angle: 8\u0026deg;; field of view (FOV): 240 mm; coronal slices: 135; voxel size: 0.937 \u0026times; 0.937 \u0026times; 1.2 mm resolution.\u003c/p\u003e\n\u003ch3\u003eVolBrain Analysis\u003c/h3\u003e\n\u003cp\u003eIn this study, automatic and quantitative analyses of MR data were conducted using the vol2Brain 1.0 pipeline. volBrain is an online platform that performs volumetric analysis of brain structures based on high-resolution T1-weighted 3D MPRAGE MRI images.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Historically, brain volume segmentation and quantification via MRI was time-consuming and required manual procedures informed by expert neuroanatomical knowledge. However, the volBrain platform developed by Manj\u0026oacute;n and Coup\u0026eacute; enables automatic volumetric and cortical thickness analyses.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn a comparative study, a high correlation was found between manual measurements and values obtained through volBrain analysis, confirming the tool\u0026rsquo;s validity.\u0026sup2;⁹ volBrain operates without the need for specialized technical training. After registering on the system, users upload their T1-weighted brain MR images in NIfTI format. The images are then processed via distributed computing across multiple supercomputers on the volBrain web server.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe volBrain pipeline incorporates a series of preprocessing and segmentation steps to enhance input image quality and accurately distinguish between different brain structures and tissues. These steps include spatially adaptive non-local denoising, rough bias field correction, affine registration to MNI space, fine-level SPM-based bias correction, intensity normalization, non-local intracranial cavity extraction (NICE), tissue classification, non-local hemisphere segmentation (NABS), and non-local subcortical structure segmentation.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe system analyzes 135 brain regions\u0026mdash;including intracranial cavity (ICV), white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), cerebrum, cerebellum, brainstem, and subcortical gray matter (sGM)\u0026mdash;while accounting for demographic factors such as age and sex.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Tissue volumes are reported in absolute values (cm\u0026sup3;) and as percentage ratios of each structure's volume relative to the intracranial volume. Additionally, an asymmetry index is calculated based on the difference between right and left hemisphere volumes relative to their mean, and this is also expressed as a percentage.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e In the present study, percentage values obtained from volBrain were used for statistical analysis.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were conducted using SPSS version 27 (IBM Corporation, Armonk, NY, USA) and JASP version 0.9. Levene\u0026rsquo;s F-test was initially applied to assess the homogeneity of variance between groups. When variance was found to be homogeneous, independent samples t-tests were used to examine whether brain volume differences between the FM and HC groups were statistically significant. Given the large number of brain regions analyzed (a total of 135), particular attention was paid to volumetric changes observed in specific areas of the pain matrix and related structures. A 95% confidence interval was adopted for all tests, and a \u003cem\u003ep\u003c/em\u003e-value less than 0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003eConsidering the large number of brain regions analyzed (n\u0026thinsp;=\u0026thinsp;135), and to address the inflation of Type I error due to multiple comparisons, the False Discovery Rate (FDR) correction method proposed by Benjamini and Hochberg (1995) was applied to all \u003cem\u003ep\u003c/em\u003e-values.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e This method is widely used in neuroimaging studies involving multiple parallel tests, as it controls the expected proportion of false positives among statistically significant findings.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e The application of the Benjamini-Hochberg FDR procedure to the comprehensive set of independent sample t-tests effectively distinguished robust findings from those that may have reached significance by chance. This refinement is a crucial step as it allows for more reliable interpretation of the results, highlights only the most robust effects, and helps prevent the overstatement of findings.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eDemographic Characteristics\u003c/h2\u003e\u003cp\u003eThe study sample consisted of 32 female FM patients aged 22\u0026ndash;79 years and 31 female HC participants aged 24\u0026ndash;56 years. The mean age of the FM group was 44.72\u0026thinsp;\u0026plusmn;\u0026thinsp;12.63 years, while the HC group had a mean age of 37.87\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29 years. No statistically significant difference in age was observed between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.102).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eVolumetric Analyses\u003c/h3\u003e\n\u003cp\u003eGroup comparisons revealed significant volumetric differences in brain structures between FM patients and HC participants (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). FM patients exhibited significantly greater total white matter (WM) volume (473.086\u0026thinsp;\u0026plusmn;\u0026thinsp;47.035 cm\u0026sup3;) compared to HC (380.202\u0026thinsp;\u0026plusmn;\u0026thinsp;92.292 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Similarly, subcortical gray matter (sGM) volume was significantly increased in the FM group (40.988\u0026thinsp;\u0026plusmn;\u0026thinsp;2.983 cm\u0026sup3;) compared to HC (34.043\u0026thinsp;\u0026plusmn;\u0026thinsp;6.922 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eAdditionally, the total limbic system volume (38.599\u0026thinsp;\u0026plusmn;\u0026thinsp;3.628 cm\u0026sup3;), right limbic volume (19.032\u0026thinsp;\u0026plusmn;\u0026thinsp;2.182 cm\u0026sup3;), and left limbic volume (19.568\u0026thinsp;\u0026plusmn;\u0026thinsp;1.626 cm\u0026sup3;) were significantly lower in FM patients than in HC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eSpecific brain regions in FM patients also showed significant volume increases. The right amygdala volume was significantly larger in FM (0.971\u0026thinsp;\u0026plusmn;\u0026thinsp;0.078 cm\u0026sup3;) compared to HC (0.870\u0026thinsp;\u0026plusmn;\u0026thinsp;0.130 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Total amygdala volume (1.920\u0026thinsp;\u0026plusmn;\u0026thinsp;0.171 cm\u0026sup3; vs. 1.762\u0026thinsp;\u0026plusmn;\u0026thinsp;0.240 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), total hippocampal volume (8.148\u0026thinsp;\u0026plusmn;\u0026thinsp;0.620 cm\u0026sup3; vs. 7.337\u0026thinsp;\u0026plusmn;\u0026thinsp;1.073 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and total thalamic volume (11.879\u0026thinsp;\u0026plusmn;\u0026thinsp;1.155 cm\u0026sup3; vs. 7.574\u0026thinsp;\u0026plusmn;\u0026thinsp;3.776 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) were also significantly greater in the FM group.\u003c/p\u003e\u003cp\u003eConversely, several brain regions exhibited significant volumetric reductions in the FM group. Cerebellar WM volume was lower in FM patients (30.887\u0026thinsp;\u0026plusmn;\u0026thinsp;3.350 cm\u0026sup3;) compared to HC (36.221\u0026thinsp;\u0026plusmn;\u0026thinsp;7.288 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Total insular cortex volume was significantly reduced in FM (27.302\u0026thinsp;\u0026plusmn;\u0026thinsp;2.909 cm\u0026sup3;) compared to HC (29.167\u0026thinsp;\u0026plusmn;\u0026thinsp;3.954 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), along with the left insula volume (14.015\u0026thinsp;\u0026plusmn;\u0026thinsp;1.468 cm\u0026sup3; vs. 15.124\u0026thinsp;\u0026plusmn;\u0026thinsp;2.116 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), and total anterior insula volume (7.666\u0026thinsp;\u0026plusmn;\u0026thinsp;0.644 cm\u0026sup3; vs. 8.391\u0026thinsp;\u0026plusmn;\u0026thinsp;0.935 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Additionally, both right anterior insula volume (3.816\u0026thinsp;\u0026plusmn;\u0026thinsp;0.346 cm\u0026sup3; vs. 4.229\u0026thinsp;\u0026plusmn;\u0026thinsp;0.522 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and left anterior insula volume (3.850\u0026thinsp;\u0026plusmn;\u0026thinsp;0.339 cm\u0026sup3; vs. 4.162\u0026thinsp;\u0026plusmn;\u0026thinsp;0.470 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) were significantly smaller in FM.\u003c/p\u003e\u003cp\u003eAmong the key components of the limbic system, total anterior cingulate gyrus (ACG) volume was significantly reduced in FM (10.319\u0026thinsp;\u0026plusmn;\u0026thinsp;1.370 cm\u0026sup3;) compared to HC (11.741\u0026thinsp;\u0026plusmn;\u0026thinsp;1.917 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), as were right ACG (4.942\u0026thinsp;\u0026plusmn;\u0026thinsp;0.931 cm\u0026sup3; vs. 5.548\u0026thinsp;\u0026plusmn;\u0026thinsp;0.908 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and left ACG (5.377\u0026thinsp;\u0026plusmn;\u0026thinsp;0.606 cm\u0026sup3; vs. 6.193\u0026thinsp;\u0026plusmn;\u0026thinsp;1.161 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) volumes. Similarly, total medial cingulate gyrus (MCG) volume (9.736\u0026thinsp;\u0026plusmn;\u0026thinsp;1.051 cm\u0026sup3; vs. 12.076\u0026thinsp;\u0026plusmn;\u0026thinsp;2.016 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), right MCG (4.831\u0026thinsp;\u0026plusmn;\u0026thinsp;0.668 cm\u0026sup3; vs. 5.863\u0026thinsp;\u0026plusmn;\u0026thinsp;0.940 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and left MCG (4.904\u0026thinsp;\u0026plusmn;\u0026thinsp;0.548 cm\u0026sup3; vs. 6.214\u0026thinsp;\u0026plusmn;\u0026thinsp;1.147 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) were significantly lower in FM patients. Significant volumetric differences were also found in the nucleus accumbens (NA), with FM patients showing reduced total NA volume (0.633\u0026thinsp;\u0026plusmn;\u0026thinsp;0.129 cm\u0026sup3;) compared to HC (0.534\u0026thinsp;\u0026plusmn;\u0026thinsp;0.139 cm\u0026sup3;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). Both right (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017) and left (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) NA volumes were also significantly lower in the FM group.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of Brain Regions Showing Significant Volume Differences (cm\u0026sup3;) Between FM and Control Groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVolume\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFM (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHC (n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"1\" nameend=\"c6\" namest=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal WM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e473.086\u0026thinsp;\u0026plusmn;\u0026thinsp;47.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e380.202\u0026thinsp;\u0026plusmn;\u0026thinsp;92.292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c6\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWM (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e237.282\u0026thinsp;\u0026plusmn;\u0026thinsp;24.071\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e195.771\u0026thinsp;\u0026plusmn;\u0026thinsp;44.239\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWM (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e235.804\u0026thinsp;\u0026plusmn;\u0026thinsp;23.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e184.431\u0026thinsp;\u0026plusmn;\u0026thinsp;48.369\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e167.765\u0026thinsp;\u0026plusmn;\u0026thinsp;36.457\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e221.877\u0026thinsp;\u0026plusmn;\u0026thinsp;62.682\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubkortikal GM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.988\u0026thinsp;\u0026plusmn;\u0026thinsp;2.983\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.043\u0026thinsp;\u0026plusmn;\u0026thinsp;6.922\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebral Hemisphere (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e508.436\u0026thinsp;\u0026plusmn;\u0026thinsp;42.292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e459.768\u0026thinsp;\u0026plusmn;\u0026thinsp;67.908\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebral Hemisphere (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e507.308\u0026thinsp;\u0026plusmn;\u0026thinsp;41.261\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e447.547\u0026thinsp;\u0026plusmn;\u0026thinsp;72.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerebellum WM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30.887\u0026thinsp;\u0026plusmn;\u0026thinsp;3.350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36.221\u0026thinsp;\u0026plusmn;\u0026thinsp;7.288\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsular Cortex (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.302\u0026thinsp;\u0026plusmn;\u0026thinsp;2.909\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.167\u0026thinsp;\u0026plusmn;\u0026thinsp;3.954\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsular Cortex (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.015\u0026thinsp;\u0026plusmn;\u0026thinsp;1.468\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.124\u0026thinsp;\u0026plusmn;\u0026thinsp;2.116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Insula (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.666\u0026thinsp;\u0026plusmn;\u0026thinsp;0.644\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.391\u0026thinsp;\u0026plusmn;\u0026thinsp;0.935\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Insula (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.816\u0026thinsp;\u0026plusmn;\u0026thinsp;0.346\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.229\u0026thinsp;\u0026plusmn;\u0026thinsp;0.522\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Insula (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.850\u0026thinsp;\u0026plusmn;\u0026thinsp;0.339\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.162\u0026thinsp;\u0026plusmn;\u0026thinsp;0.470\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLimbic System (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.599\u0026thinsp;\u0026plusmn;\u0026thinsp;3.628\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.979\u0026thinsp;\u0026plusmn;\u0026thinsp;4.798\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLimbic System (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.032\u0026thinsp;\u0026plusmn;\u0026thinsp;2.182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.275\u0026thinsp;\u0026plusmn;\u0026thinsp;2.160\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLimbic System (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.568\u0026thinsp;\u0026plusmn;\u0026thinsp;1.626\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.705\u0026thinsp;\u0026plusmn;\u0026thinsp;2.761\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmygdala (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.920\u0026thinsp;\u0026plusmn;\u0026thinsp;0.171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.762\u0026thinsp;\u0026plusmn;\u0026thinsp;0.240\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmygdala (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.971\u0026thinsp;\u0026plusmn;\u0026thinsp;0.078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.870\u0026thinsp;\u0026plusmn;\u0026thinsp;0.130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.633\u0026thinsp;\u0026plusmn;\u0026thinsp;0.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.534\u0026thinsp;\u0026plusmn;\u0026thinsp;0.139\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.305\u0026thinsp;\u0026plusmn;\u0026thinsp;0.064\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.263\u0026thinsp;\u0026plusmn;\u0026thinsp;0.073\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.328\u0026thinsp;\u0026plusmn;\u0026thinsp;0.068\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.271\u0026thinsp;\u0026plusmn;\u0026thinsp;0.072\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal Forebrain (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.699\u0026thinsp;\u0026plusmn;\u0026thinsp;0.106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.593\u0026thinsp;\u0026plusmn;\u0026thinsp;0.131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal Forebrain (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.363\u0026thinsp;\u0026plusmn;\u0026thinsp;0.056\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.294\u0026thinsp;\u0026plusmn;\u0026thinsp;0.075\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal Forebrain (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.336\u0026thinsp;\u0026plusmn;\u0026thinsp;0.059\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.298\u0026thinsp;\u0026plusmn;\u0026thinsp;0.062\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.319\u0026thinsp;\u0026plusmn;\u0026thinsp;1.370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.741\u0026thinsp;\u0026plusmn;\u0026thinsp;1.917\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.942\u0026thinsp;\u0026plusmn;\u0026thinsp;0.931\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.548\u0026thinsp;\u0026plusmn;\u0026thinsp;0.908\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.377\u0026thinsp;\u0026plusmn;\u0026thinsp;0.606\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.193\u0026thinsp;\u0026plusmn;\u0026thinsp;1.161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.736\u0026thinsp;\u0026plusmn;\u0026thinsp;1.051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.076\u0026thinsp;\u0026plusmn;\u0026thinsp;2.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.831\u0026thinsp;\u0026plusmn;\u0026thinsp;0.668\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.863\u0026thinsp;\u0026plusmn;\u0026thinsp;0.940\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.904\u0026thinsp;\u0026plusmn;\u0026thinsp;0.548\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.214\u0026thinsp;\u0026plusmn;\u0026thinsp;1.147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHippocampus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.148\u0026thinsp;\u0026plusmn;\u0026thinsp;0.620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.337\u0026thinsp;\u0026plusmn;\u0026thinsp;1.073\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHippocampus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.107\u0026thinsp;\u0026plusmn;\u0026thinsp;0.294\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.639\u0026thinsp;\u0026plusmn;\u0026thinsp;0.611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHippocampus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.041\u0026thinsp;\u0026plusmn;\u0026thinsp;0.341\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.698\u0026thinsp;\u0026plusmn;\u0026thinsp;0.511\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.879\u0026thinsp;\u0026plusmn;\u0026thinsp;1.155\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.574\u0026thinsp;\u0026plusmn;\u0026thinsp;3.776\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.892\u0026thinsp;\u0026plusmn;\u0026thinsp;0.542\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.714\u0026thinsp;\u0026plusmn;\u0026thinsp;1.906\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.987\u0026thinsp;\u0026plusmn;\u0026thinsp;0.628\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.860\u0026thinsp;\u0026plusmn;\u0026thinsp;1.878\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAngular Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.847\u0026thinsp;\u0026plusmn;\u0026thinsp;1.179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.966\u0026thinsp;\u0026plusmn;\u0026thinsp;2.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupramarginal Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.771\u0026thinsp;\u0026plusmn;\u0026thinsp;1.082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.442\u0026thinsp;\u0026plusmn;\u0026thinsp;1.123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18.320\u0026thinsp;\u0026plusmn;\u0026thinsp;2.293\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.419\u0026thinsp;\u0026plusmn;\u0026thinsp;2.549\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.099\u0026thinsp;\u0026plusmn;\u0026thinsp;1.232\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.023\u0026thinsp;\u0026plusmn;\u0026thinsp;1.351\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.221\u0026thinsp;\u0026plusmn;\u0026thinsp;1.231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.396\u0026thinsp;\u0026plusmn;\u0026thinsp;1.296\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eWM: White Matter, GM: Gray Matter, CSF: Cerebrospinal Fluid, R: Right, L: Left\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eFDR-Corrected Brain Volume Analysis Results\u003c/h3\u003e\n\u003cp\u003eFollowing FDR correction, a substantial number of brain regions retained statistical significance, indicating robust and reliable group differences. The most prominent findings were observed in subcortical and white matter structures. In particular, the thalamus (total, right, and left volumes), total white matter in both hemispheres, and cerebral white matter exhibited highly significant differences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). Core components of the limbic system\u0026mdash;including the amygdala (especially the right side), bilateral nucleus accumbens, basal forebrain also remained significant after FDR adjustment. Additionally, several cortical regions, notably the anterior and medial cingulate cortex, postcentral gyrus, frontal pole, medial segments of the superior frontal gyrus, and the supplementary motor cortex, survived correction. The consistency of these findings across related structures (e.g., bilateral thalamus and multiple frontal regions) further strengthens the overall results.\u003c/p\u003e\u003cp\u003eConversely, several variables that initially reached significance at the conventional \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05 threshold did not survive FDR correction. These less robust or potentially false-positive findings include the right angular gyrus, supramarginal gyrus, left inferior frontal gyrus (pars triangularis), and the left medial frontal cortex. The loss of significance in these specific cortical areas suggests that, while subtle differences may exist, they are not strong enough to be distinguished from noise once false discovery rates are controlled.\u003c/p\u003e\u003cp\u003eThe implementation of the FDR correction thus yielded a clear and focused pattern of brain volume differences based on rigorous multiple comparison adjustments. This approach confirms that the volumetric differences observed between the FM and HC groups are statistically meaningful and reliable, rather than attributable to random variation.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTablo 2. FDR-Adjusted Brain Volume Comparisons Between FM and HC Groups\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003edf\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003et\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value(FDR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDirection\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWM (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubcortical GM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThalamus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrum WM (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrum WM (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrum WM (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLimbic System (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmygdala (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmygdala (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNucleus Accumbens (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal Forebrain (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal Forebrain (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnterior Cingulate Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-5.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-5.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Cingulate Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-5.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-2.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostcentral Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-3.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFrontal Pole total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSup. Frontal Gyrus medial segment (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e49.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSup. Frontal Gyrus medial segment (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSup. Frontal Gyrus medial segment (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupplementary Motor Cortex (Total)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAngular Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-2.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSupramarginal Gyrus (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-2.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTriangular Inf. Frontal Gyrus (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedial Frontal Cortex (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eWM: White Matter, GM: Gray Matter, R: Right, L: Left; \u0026uarr; FM\u0026thinsp;\u0026gt;\u0026thinsp;HC\u0026thinsp;=\u0026thinsp;Increased volume in FM group compared to controls ; \u0026darr; FM\u0026thinsp;\u0026lt;\u0026thinsp;HC\u0026thinsp;=\u0026thinsp;Decreased volume in FM group compared to controls; * = Survived FDR correction (significant)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary objective of the present study was to detect volumetric changes in brain structures associated with FM using artificial intelligence-assisted MRI analysis, thereby contributing to a better understanding of the neural signature patterns of FM and chronic pain. Recent investigations provide increasing evidence that chronic pain in FM leads to structural,\u003csup\u003e33\u003c/sup\u003e functional\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e and neurochemical changes in brain architecture.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e In this context, our study demonstrates striking volumetric-brain alteration patterns in FM compared with HC. Initial analyses revealed increases in total WM and sGM volumes in FM. Although volumetric studies have predominantly focused on GM, previous FM research likewise points to structural abnormalities in WM.\u003csup\u003e38,39\u003c/sup\u003e In a systematic review, findings from 10 DTI studies involving a total of 215 FM patients were evaluated, revealing widespread structural disruption in WM organization, including in regions such as the thalamus, frontal cortex, and corpus callosum.\u0026sup3;⁹ Similarly, a volumetric and DTI-based study\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e found increased FA values in the superior frontal gyrus and ACG, which were significantly associated with pain and fatigue severity. The positive correlation of WM changes in FM with symptom severity may reflect maladaptive neuroplastic processes within the CNS that contribute to symptom exacerbation rather than protection.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Hemispheric analyses revealed significant reductions in basal forebrain volume in both right and left hemispheres, with the reduction in the right hemisphere (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) being more pronounced than the left (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018). Literature indicates that the right hemisphere is more involved in alertness, broad attentional processes and processing of external stimuli, whereas the left hemisphere predominates in language and goal-directed attention.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e The more marked right-hemisphere reduction may represent a neuroanatomical mechanism underlying attentional deficits and heightened sensitivity to external stimuli (hypervigilance) in FM.\u003c/p\u003e\u003cp\u003eIn addition to these global changes, we focused on specific brain regions impacted by volumetric alterations. The FM group exhibited a statistically significant decrease in cerebellar WM volume. Cerebellar changes in FM have also been reported in previous studies.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e Although the cerebellum has long been considered a secondary structure in pain research, current literature indicates that it plays an active role in the pain-processing network.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e Because of its connections to the cerebral cortex, brainstem and limbic system, the cerebellum contributes to both sensory and affective components of pain.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e It has been further demonstrated that the cerebellum receives nociceptive inputs directly, can be activated by painful stimuli, and plays both pronociceptive and antinociceptive roles, as well as a role in coordinating pain-related motor responses and behavioural adaptations.⁴⁵ In a study examining the relationship between cerebellar structural changes and clinical symptomatology in FM, significant reductions in myelination levels were detected in left cerebellar lobules VI and VIII, and these changes were shown to correlate with anxiety levels.\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e The structural cerebellar alterations detected in FM may thus be directly related to clinical symptomatology. Given the cerebellum\u0026rsquo;s involvement in both pain modulation and cognitive function,\u003csup\u003e46\u003c/sup\u003e these structural changes suggest that FM patients may face difficulties in managing the cognitive and emotional dimensions of chronic pain.\u003c/p\u003e\u003cp\u003eStructural changes in the limbic system were examined in detail. We found a significant reduction in total limbic system volume in FM, consistent with previous neuroimaging data.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e The limbic system\u0026mdash;comprising the amygdala, hippocampus, thalamus and ACG\u0026mdash;is central to pain perception, emotional regulation, memory, interoception and autonomic responses.\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e Volume losses in this system may underlie the increased pain sensitivity and impaired stress regulation frequently reported in FM. Region-specific analyses revealed significant reductions in ACG and MCG volumes in FM. These regions are key to cognitive appraisal of pain and regulation of emotional responses.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e These findings indicate impaired cognitive\u0026ndash;affective regulation of pain and disrupted functional integrity at the limbic system level.\u003c/p\u003e\u003cp\u003eAnother key finding involved the thalamus: consistent with earlier research,\u003csup\u003e16,52\u003c/sup\u003e we observed increased total thalamic volume in FM. The thalamus serves as a central relay for nociceptive signals to the cortex.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e Dysfunctional thalamic signalling in FM has been associated with disturbed transmission of nociceptive signals.\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e This impaired transmission may lower pain thresholds and contribute to central sensitization in FM.\u003csup\u003e55\u003c/sup\u003e The structural changes observed in the thalamus may play a role in mechanisms of brain\u0026ndash;pain transition from localized pain to widespread allodynia in chronic pain conditions.\u003c/p\u003e\u003cp\u003eIn group comparisons, the amygdala\u0026mdash;a further component of the limbic system\u0026mdash;was found to have larger volume in FM. The amygdala plays a prominent role in processing fear-related emotions and emotionally associated memory.\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e Previous studies have indicated that the amygdala is activated by pain-related fear and plays a central role not only in sensory pain processing but also in associated emotional and motivational processes.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e The increase in amygdala volume in FM supports the notion that amygdala plasticity plays a key role in the affective component of chronic pain. Our analyses also revealed hemispheric lateralization of amygdala changes in FM; consistent with previous findings, we found a particularly marked volume increase in the right amygdala.\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e Prior work suggests that right-amygdala enlargement is associated with threat perception, fear responses and rapid emotional reactions,\u003csup\u003e62\u003c/sup\u003e while left-amygdala changes are more linked to complex emotional evaluation, cognitive control and verbal expression of emotions.\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e The comparatively limited volume increase in the left amygdala may indicate differing hemispheric involvement. This lateralization may be an important finding for understanding individual differences in pain perception and emotional responses in FM. While prominent right-amygdala changes may explain FM\u0026rsquo;s effects on emotional responses and pain-related threat perception, changes in the left amygdala may represent neural substrates of broader cognitive and emotional dysregulation. Our analyses also showed increased hippocampal volume in FM. The hippocampus, particularly the DG, plays a crucial role in memory formation and processing, including pain-related memory.\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e Chronic pain has been shown to impair hippocampus-dependent cognitive functions and lead to memory deficits.\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e,\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e Neuroplastic changes in the hippocampus observed in FM may contribute to the formation of persistent pain memories, thus affecting emotional responses and cognitive appraisal of pain.\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e This suggests that in FM, pain may transform into a continuous recall process and contribute to intensification of pain perception via a possible neurobiological mechanism.\u003c/p\u003e\u003cp\u003eWe found significant reductions in volumes of the insular cortex (IK) and anterior insula (AIns) in FM\u0026mdash;regions critical for pain perception, interoceptive awareness and emotional regulation.\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e The structural changes observed may disrupt the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis regulation\u0026mdash;an important controller of stress responses.\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e While the HPA axis normally functions adaptively under acute stress, in chronic pain conditions such as FM it may become dysfunctional, contributing to persistent stress load via inadequate or irregular cortisol responses.\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e HPA axis dysfunction is considered a possible pathway that adds to chronic stress load and insufficient cortisol responses,\u003csup\u003e71\u003c/sup\u003e thereby intensifying symptoms in chronic pain disorders like FM. ndeed, limbic self neuromodulation interventions targeting limbic anomalies in fibromyalgia may reduce symptom severity and overall disease burden, as shown in recent studies.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAdditionally, volumetric analyses revealed significant reductions in NA total volume and its hemispheric subregions in FM. The NA plays a key role in reward processing, motivation, emotional regulation and pain modulation.\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e Disruption of NA-related reward mechanisms is frequently linked to anhedonia, motivation loss and emotional stress.\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e In this context, the volume loss in the NA in FM may reflect not only the physical pain component but also the psychological and emotional burden of the condition. The more pronounced loss in the left NA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002 vs. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017 for right) may be relevant since the left NA has been found to play a more active role in reward expectancy, emotional evaluation and processing of social-hedonic stimuli,\u003csup\u003e75\u003c/sup\u003e whereas the right NA is more closely associated with reward sensitivity and motivational functions.\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u003c/sup\u003e The lateralization effect seen in the left NA might thus provide a neuroanatomical basis for symptoms such as anhedonia, emotional blunting and motivational loss common in FM.\u003c/p\u003e\u003cp\u003eThe findings support the view that FM is a complex, centrally mediated pain syndrome with a distinct neural-signature pattern in the CNS, offering a specific neurobiological profile and important insight into the central pathophysiology of the condition.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis study's findings are constrained by a relatively small sample size, limiting generalizability. Furthermore, the cross-sectional design prevents the assessment of longitudinal changes in FM. Future research should employ larger samples and longitudinal methods to address these limitations.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study revealed specific volumetric alterations in the central nervous system of FM patients. Structural differences in the limbic system, thalamus, hippocampus, amygdala, and insular cortex reflect neuroplastic processes affecting the sensory, emotional, and cognitive components of pain. Increased WM volumes and reductions in reward-related structures further support the conceptualization of FM as a centrally mediated, complex pain disorder. The use of AI-assisted platforms such as volBrain offers an effective, non-invasive approach to elucidating the neurobiological underpinnings of FM. Identifying these structural signatures may enhance diagnostic accuracy and support the development of personalized and targeted therapeutic strategies. Ultimately, this study emphasizes the significance of neuroimaging-based approaches in elucidating FM's underlying mechanisms and the need for neurobiologically informed, integrative pain management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConsent Statement: This retrospective study was conducted using anonymized MRI data retrieved from the hospital archive of fibromyalgia patients. The study received approval from the \u0026Uuml;sk\u0026uuml;dar University Ethics Committee under protocol number 61351342/JAN 2024-101. The requirement for individual patient consent was waived due to the retrospective and anonymized nature of the data.\u003c/p\u003e\u003cp\u003e\u003ch2\u003eUse of AI-Assisted Tools\u003c/h2\u003e\u003cp\u003eAI-assisted tools were used in the preparation of this manuscript. Specifically, SciSpace was used to identify and filter relevant academic studies, and ChatGPT (OpenAI) was used to support the clarity, academic tone, and narrative flow of the text. The authors reviewed and verified all generated content and take full responsibility for the final manuscript.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eWe thank Aslınur \u0026Ccedil;akmak for her significant contributions to the technical aspects of the study, as well as Dr. Necati Alp Tabak and Sedat Aydın for their support in providing MRI data for fibromyalgia patients.\u003c/p\u003e\u003ch2\u003eData Availability Statement\u003c/h2\u003e\u003cp\u003eThe MRI data analyzed during this study were retrospectively obtained from the archive of NPIstanbul Brain Hospital. All data were fully anonymized prior to analysis. Ethical approval was obtained from the \u0026Uuml;sk\u0026uuml;dar University Ethics Committee (Protocol No: 61351342/JAN 2024\u0026thinsp;\u0026minus;\u0026thinsp;101). Due to ethical and privacy considerations, the datasets are not publicly available but can be made available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGoren A, Mould-Quevedo J, daCosta DiBonaventura M (2014) Prevalence of pain reporting and associated health outcomes across emerging markets and developed countries. 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Front Behav Neurosci 18. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnbeh.2024.1420028\u003c/span\u003e\u003cspan address=\"10.3389/fnbeh.2024.1420028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Üsküdar University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fibromyalgia, Chronic Pain, Pain Matrix, MRI Imaging, Brain Structures","lastPublishedDoi":"10.21203/rs.3.rs-8186703/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8186703/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eFibromyalgia (FM) is a chronic pain syndrome predominantly affecting women, characterized by widespread pain, sensory hypersensitivity, fatigue, and sleep disturbances. Recent evidence suggests that chronic pain in FM is closely associated with dysfunctions in the central nervous system (CNS). This study aims to identify volumetric brain changes observed in FM patients and to evaluate the relationship between these structural alterations and neural plasticity mechanisms.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe study included 32 female patients diagnosed with FM (aged 22\u0026ndash;79 years; mean age: 44.72\u0026thinsp;\u0026plusmn;\u0026thinsp;12.63) and 31 age- and sex-matched healthy controls (aged 24\u0026ndash;56 years; mean age: 37.87\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29). There was no significant age difference between the groups (p\u0026thinsp;=\u0026thinsp;0.102). High-resolution T1-weighted magnetic resonance imaging (MRI) data were analyzed using the vol2Brain module of the volBrain platform. Volumetric measurements were obtained for 135 distinct brain regions.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eVolumetric analyses revealed marked changes in the limbic system structures of FM patients. Increased volumes were observed in the thalamus, amygdala, and hippocampus, whereas the anterior and medial cingulate gyri and insular cortex exhibited decreased volumes. Additional findings included an increase in total white matter (WM) and subcortical gray matter, along with a reduction in cerebellar WM volume.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe results underscore the neurobiological basis of FM and suggest that the observed structural changes are linked to neural plasticity mechanisms within the CNS. Identifying FM-specific volumetric alterations may support the development of personalized and targeted therapeutic interventions.\u003c/p\u003e","manuscriptTitle":"Volumetric MRI Analysis of the Brain Pain Matrix in Fibromyalgia: Unraveling the Structural Changes and Neural Mechanisms of Chronic Pain","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 17:57:40","doi":"10.21203/rs.3.rs-8186703/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1a5ba0b6-73f2-4243-9a48-72b52e72489a","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58460344,"name":"Anesthesiology \u0026 Pain Medicine"},{"id":58460345,"name":"Computational Neuroscience"},{"id":58460346,"name":"Neurobiology of Disease"}],"tags":[],"updatedAt":"2025-12-02T17:57:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 17:57:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8186703","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8186703","identity":"rs-8186703","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}