Exploring Neural Signaling Patterns and Their Physiological Origins in Fibromyalgia by Means of Functional MRI Guided by a Review of the Literature

Abstract

Background/objectives: Fibromyalgia (FM) is a chronic pain condition that includes symptoms of hyperalgesia and has an unknown etiology. This study aimed to further investigate the underlying neural signaling mechanisms and their relation to observed blood oxygenation-level dependent (BOLD) signal increases at the onset of functional magnetic resonance imaging (fMRI) runs.

Methods: The possible neural mechanisms were first explored by reviewing the current literature. The second component of this study involved a voxel-by-voxel analysis of BOLD responses in all regions of the brain. The fMRI data were obtained from a previous study of participants with and without fibromyalgia during fMRI runs involving either a noxious heat pain stimulus or no stimulus.

Results: The literature review indicates that no single factor can explain the initial BOLD signal rise observed in FM but that there are likely multiple interacting influences. These include physiological dysregulation via mechanisms, such as oxidative stress, mitochondrial dysfunction, and cytokine activity, and may involve the sympathetic nervous system. The analysis of BOLD responses demonstrated that the initial BOLD rises occur specifically in gray matter regions and are largest in regions involved with pain processing, including the right insular cortex and periaqueductal gray region. Moreover, the BOLD rise is significantly larger in people with FM prior to the application of a noxious stimulus.

Conclusions: The initial rise in BOLD response demonstrates heightened metabolic demand that is exaggerated in people with FM. It appears to be influenced by cognitive factors such as anticipation and may reflect neural dysregulation, possibly involving autonomic signaling.

Keywords: analysis; brain; brainstem; fibromyalgia; functional MRI; pain; physiology; review.

Figure 1

Flow chart depicting article selection process used to conduct literature analysis following PRISMA guidelines.

Figure 2

Functional MRI paradigm for conditions with and without noxious heat stimulation conditions [22]. The timeline shows when participants were told whether or not they would experience the painful condition or not at time points A and D, when the noxious stimulus was administered at point B, and when the participants were asked to voice their pain ratings to the first and last heat contacts at point C.

Figure 3

Illustration of the method used to estimate the initial rise in BOLD response in each voxel of each fMRI run. BOLD signal change values are fit to linear functions for the periods 8–40 s and 40–270 s (the fits are shown with red lines) in order to reliably determine the intensity values at 8 s and 40 s (indicated with vertical dashed lines). The horizontal dashed lines indicate the signal values at these times, for the example shown. Note that the data shown are the average across the entire FM study group and that actual data from each participant are much noisier than is depicted in this example. The yellow band indicates the period when participants were informed of the stimulus type to expect, and the green band indicates the stimulation period.

Figure 4

Images in radiological orientation depicting the magnitude of the initial rise in BOLD signal in each voxel averaged within each of the four groups. (a) Transverse (left) and coronal (right) slices showing results in the FM stim (n = 84) group/condition. The slice locations were centered on the highest signal change region in this group. (b) Transverse and coronal slices at the same locations as in frame a in the FM rest (n = 79) group. (c) Corresponding transverse and coronal slices showing results in the HC stim (n = 63) group. (d) Again, corresponding slices in the HC rest (n = 66) group. Colors indicate the magnitude of the initial rise response with red being highest, decreasing through orange, then yellow, and green being the lowest values above the chosen threshold.