Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying. The name "myalgic encephalomyelitis" essentially means "muscle pain related to central nervous system inflammation" and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable. We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine "profile" for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.