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 functional34,35 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 study40 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.