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

Pardo, José V., MD, PhD*,†; Larson, Robert C., BS; Spencer, Rachel J., DVM; Lee, Joel T., MSEE*; Pasley, Jeffrey D., PhD§; Torkelson, Carolyn J., MD; Larson, Alice A., PhD

The Clinical Journal of Pain: May 2019 - Volume 35 - Issue 5 - p 407–419
doi: 10.1097/AJP.0000000000000695
Original Articles

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 18F-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.

*Cognitive Neuroimaging Unit, Minneapolis VA Health Care System

Departments of Psychiatry

Family Medicine and Community Health, University of Minnesota, Minneapolis

Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN

§School of Science and Technology, Georgia Gwinnett College, Lawrenceville, GA

All human studies were approved and monitored by the Institutional Review Board of the University of Minnesota (IRB Study #1007M85352) in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

The scripts for the analysis of PET scans are available upon request from J.T.L.

J.V.P. worked together with A.A.L. in the design of the project and supervised the analysis of PET data; R.C.L.: was the study coordinator; R.J.S.: analyzed data and contributed to the writing of the final manuscript; J.T.L.: developed and applied the new statistical analysis of PET scans; J.D.P.: assisted in the design of the studies and the collection of samples from patients; C.J.T.: confirmed the patient data eliminating conditions that may have contributed to the patients’ reported pain other than FMS; and A.A.L.: conceived the project and wrote the final manuscript.

Supported by a grant to A.A.L. and J.V.P. from NIH (Washington, DC) from the National Institutes on Arthritis and Musculoskeletal and Skin Diseases [AR056092], to J.V.P. from the Veterans Administration [5I01CX000501] (Washington, DC), to J.V.P. from the Clinical and Translational Science Award (CTSA) UL1TR000114 (Washington, DC), the Department of Veterans Affairs (Minneapolis, MN), and to A.A.L., J.V.P., and J.D.P. from the University of Minnesota Graduate School (Minneapolis, MN). The remaining authors declare no conflict of interest.

Reprints: Alice A. Larson, PhD, Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, Rm 295 Animal Science Veterinary Medicine Building, Saint Paul, MN 55108 (e-mail:

Received October 9, 2018

Received in revised form January 23, 2019

Accepted February 4, 2019

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