Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by profound fatigue lasting at least 6 months and accompanied by numerous somatic symptoms. Infectious, immunological, neuroendocrine, sleep, and psychological mechanisms for ME/CFS have been investigated but a unifying etiology has yet to emerge. We hypothesize that peripheral tissue abnormalities significantly contribute to ME/CFS pathogenesis. Amongst other features, patients with ME/CFS have substantial abnormalities of intramuscular metabolites following a standardized exercise challenge and metabolite efflux from ME/CFS muscles is significantly lower than in NC immediately post-exercise. We propose that accumulation of these metabolites results in stimulation of ERGOreceptors (ERGO) (afferents sensitive to muscle metabolites) and nociceptors in muscles with resulting autonomic nervous system (ANS), HPAaxis, fatigue, and pain pathway activation. Excessive activation of these pathways then leads to characteristic ME/CFS symptoms including profound fatigue and often pain. We hypothesize that these pathways have become sensitized in ME/CFS resulting in amplification of peripheral signals to the CNS. We will characterize ME/CFS subjects' peripheral contributions to fatigue and pain including sensitized ERGO and nociceptor pathways using the post-handgrip exercise regional circulatory occlusion (PH-RCO) method and quantitative sensory testing (QST), including mechanical and heat thresholds. PH-RCO traps exercise related metabolites in muscles post exercise allowing estimates of peripheral contributions to fatigue and pain. This results in prolonged activation of ERGO and pain receptors [3] and subsequent post-exertional fatigue and pain. In order to test the relevance of ERGOs for chronic fatigue and pain we propose reducing ERGO signaling in muscles of ME/CFS patients. For this purpose we will use placebo controlled lidocaine injections into several muscle groups to reduce ERGO activity and thus ongoing fatigue and pain of ME/CFS patients. This approach holds great promise because our preliminary data have shown that such injections can result in robust reductions of fatigue and pain (Cohen's d >1.0). Thus therapeutic muscle injections may represent a clinically relevant model to study the contributions of ERGO induced fatigue and pain to ME/CFS. To estimate treatment effects on both overall fatigue and pain in ME/CFS subjects, we will utilize validated fatigue and pain assessments, including several fatigue scales and QST. Thus we will characterize overall and local effects of muscle injections on ME/CFS subjects' fatigue and pain abnormalities. In order to assess the neural correlates to fatigue and pain in ME/CFS subjects we will perform functional brain imaging (fMRI) using arterial spin labeling (ASL). We will also utilize fMRI to characterize the cerebral blood flow changes of PH-RCO related fatigue in ME/CFS compared to NC subjects. In addition, we will perform neural connectivity analyses of resting state networks before and after PHRCO which will characterize connectivity changes induced by fatigue. Overall, our proposal will help characterize peripheral and central nervous system contributions to chronic fatigue and pain in patients with ME/CFS that may lead to novel therapies for this chronic illness.

Public Health Relevance

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is complex illness associated with non-restorative sleep, pain, and abnormalities of the autonomous system and HPA-axis. Although no unifying hypothesis has been established for the pathogenesis of ME/CFS, most previous work has focuses on central nervous system factors, including infections, trauma, depression, and immune disorders. We hypothesize that peripheral signaling from metabo-receptors in muscles is strongly involved in initiating and maintaining chronic fatigue in ME/CFS. We will test the effects of activation as well as inactivation of these receptors on chronic fatigue and pain. Additionally, we will use quantitative sensory testing to test evidence for peripheral and central sensitization of these patients. Brain imaging will be used to explore the neural correlates of fatigue/pain modulation in normal controls and patients with ME/CFS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
4R01NR014049-05
Application #
9079283
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Matocha, Martha F
Project Start
2012-09-26
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Sevel, Landrew S; Boissoneault, Jeff; Letzen, Janelle E et al. (2018) Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients. Exp Brain Res 236:2245-2253
Boissoneault, Jeff; Letzen, Janelle; Robinson, Michael et al. (2018) Cerebral blood flow and heart rate variability predict fatigue severity in patients with chronic fatigue syndrome. Brain Imaging Behav :
Bartley, Emily J; Robinson, Michael E; Staud, Roland (2018) Pain and Fatigue Variability Patterns Distinguish Subgroups of Fibromyalgia Patients. J Pain 19:372-381
Boissoneault, Jeff; Sevel, Landrew; Robinson, Michael E et al. (2018) Functional brain connectivity of remembered fatigue or happiness in healthy adults: Use of arterial spin labeling. J Clin Exp Neuropsychol 40:224-233
Staud, Roland; Boissoneault, Jeff; Craggs, Jason G et al. (2018) Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. Fatigue 6:63-79
Boissoneault, Jeff; Letzen, Janelle; Lai, Song et al. (2018) Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI. Clin Physiol Funct Imaging 38:128-137
Staud, Roland; Kizer, Taylor; Robinson, Michael E (2017) Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome. J Pain Res 10:1477-1486
Stroman, Patrick W; Bosma, Rachael L; Cotoi, Andreea I et al. (2016) Continuous Descending Modulation of the Spinal Cord Revealed by Functional MRI. PLoS One 11:e0167317
Boissoneault, Jeff; Letzen, Janelle; Lai, Song et al. (2016) Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study. Magn Reson Imaging 34:603-8
Gay, Charles W; Robinson, Michael E; Lai, Song et al. (2016) Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses. Brain Connect 6:48-56

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