Exposure to Cold Unmasks Potential Biomarkers of Fibromyalgia Syndrome Reflecting Insufficient Sympathetic Responses to Stress

Abstract

Objectives: Fibromyalgia syndrome (FMS) is a chronically painful condition whose symptoms are widely reported to be exacerbated by stress. We hypothesized that female patients with FMS differ from pain-free female controls in their sympathetic responses, a fact that may unmask important biomarkers and factors that contribute to the etiology of FMS.

Materials and methods: In a pilot study, blood pressure (BP), skin temperature, thermogenic activity, circulating glucose, and pain sensitivity of 13 individuals with FMS and 11 controls at room temperature (24°C) were compared with that after exposure to cold (19°C).

Results: When measured at 24°C, BP, skin temperature, blood glucose, and brown adipose tissue (BAT) activity, measured using F-fluorodeoxyglucose positron-emission tomography/computed tomography, did not differ between controls and individuals with FMS. However, after cold exposure (19°C), BP and BAT activity increased in controls but not in individuals with FMS; skin temperature on the calf and arm decreased in controls more than in individiuals with FMS; and circulating glucose was lower in individiuals with FMS than in controls. Pain sensitivity did not change during the testing interval in response to cold.

Discussion: The convergence of the effect of cold on 4 relatively simple measures of thermogenic, cardiovascular, and metabolic activity, each regulated by sympathetic activity, strongly indicate that individuals with FMS have impaired sympathetic responses to stress that are observable and highly significant even when measured in extraordinarily small sample populations. If insufficient sympathetic responses to stress are linked to FMS, stress may unmask and maximize these potential clinical biomarkers of FMS and be related to its etiology.

Figure 1

Pain-related measurements across groups (FMS, Controls) and temperatures (Warm, Cold) show FMS patients experience more pain than controls under both temperature conditions. The pain threshold was reflected in measures of the mean ± SEM dolorimetry values obtained in patients (A). These values did not differ in individuals or in groups when recorded before, during or after exposure to either hot or cold. The McGill pain questionnaire (MPQ) further characterized sensory (B) and affective pain (C) as well as results from the visual analog scale (VAS) (D) and present pain index (PPI) (E). Individual and group values of each parameter did not differ in response to exposure to either cold or warm temperatures. Values in panels A-E were therefore averaged for each individual and represent the average (± SEM) of all time-points of each group at each temperature and analyzed using an unpaired two-tailed Student’s t-test using a cutoff of P < 0.05 for significance.

Figure 2

Distribution and intensity of pain. The mean ± SEM number of painful sites identified on a diagram of 45 possible areas of the body (A and B) and a VAS of that pain (C and D) were assessed before (A and C) and immediately after (B and D) exposure to the warm and cold temperatures. The values of healthy controls (Control) were compared to that of patients with FMS using a two-tailed unpaired Student’s t-test with a P < 0.05 as a cutoff for statistical significance, as indicated by the asterisk.

Figure 3

Physiologic changes before and during exposure to two ambient temperatures. Values represent the mean ± SEM systolic blood pressure (BP) (A); diastolic BP (B); and heart rate (HR) (C) before and 1 h after exposure to warm and cold environments in controls and in patients with FMS. All groups A-C were analyzed using paired two-tailed Student’s t-test with a cutoff of P < 0.05 for significance, as indicated by the asterisk (significant) or ‘ns’ (not significant).

Figure 4

Systolic BP after exposure to two ambient temperatures relative to subject age. Values represent age and systolic BP in controls and in patients with FMS 1 h after exposure to warm or cold environments. Pearson’s correlational analyses compared individual ages of subjects with their corresponding systolic BP values for each group 1 h after exposure to either warm or cold environment with a cutoff of P < 0.05 for significance, as indicated by the asterisk.

Figure 5.

Skin temperatures 1 h after warm and cold exposures. Values indicate the mean ± SEM temperature of skin in the ear (A), on the forehead (B), over the forearm (C), and on the calf (D) in controls and patients with FMS. Groups were compared using an unpaired, two-tailed Student’s t-test with a cutoff of P < 0.05 for significance, as indicated by the asterisk.

Figure 6

FDG uptake in PET/CT of a healthy subject at cool temperature. CT scan shows radiodensity of neck and upper chest to just below clavicle (A). Template (blue) indicates all fat superimposed on CT (B). Template was based on radiodensity difference of fat from non-fat tissues (e.g., muscle, lung). FDG uptake in PET/CT scan of control subject resting for 2.5 h in cold (62°F or 16.8°C) (C). Color scale indicates greater uptake with hotter colors. The threshold was set at 3,500 counts (i.e., blue, normalized to whole brain uptake of 20,000) or SUV = 2 based on body weight. Maximum or greater uptake indicated by white color indicating 14,000 counts or SUV 8.

Figure 7

Quantification of BAT activity after exposure to cool (62°F or 16.8°C) and warm (76°F or 24.4°C) ambient temperatures, as visualized using methods illustrated in Figure 5. Values reflect the mean ± SEM of FDG uptake in BAT in healthy controls (n = 10) and in patients with FMS (n = 12). One outlier occurred in the FMS patients in the cool condition and was retained for statistical analysis. Data were compared within groups after exposure to warm and to cold environments using paired two-tailed Student’s t-test with a cutoff of P < 0.05 for significance, as indicated by the asterisk (significant) or ‘ns’ (not significant).

Figure 8

Circulating blood glucose and its relationship to dolorimetric measures of pain threshold. Values depict the mean ± SEM concentration of glucose measured in blood samples taken immediately prior to CT scans of both groups after exposure to warm and cold environments (A). These values were compared using ANOVA using a cutoff of P < 0.05 for significance, as indicated by the asterisk. Individual changes in values for glucose (B) reflect the difference in concentrations between warm and cold environments. Using Pearson’s correlational analyses, these glucose values were compared within groups to their corresponding pain assessments obtained when tested by dolorimetric analyses (as used in figure 1). Correlation coefficients (R) and P values were calculated for each group with a P < 0.05 as the cutoff for significance.