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

Abstract

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.

Chronic fatigue syndrome: progress and possibilities

“…It has been hypothesised that fatigue and pain may cause excessive interoceptive monitoring causing a decrease in externally directed attention, which is very similar to changes associated with the acute sickness response to infection or inflammation, manifesting as an altered central perception of physical or cognitive effort . Structural neuroimaging studies (computed tomography and magnetic resonance imaging) have not revealed any consistent abnormality, but a growing body of evidence from research functional imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy and positron emission tomography, appears promising . The recognition of prevalent postural symptoms (dizziness, palpitations), and the key role the autonomic system plays in responses to stressors, has led to investigation of heart rate variability analysis, galvanic skin responses and tilt table testing to generally document evidence for sympathetic predominance, although the biological basis of this alteration remains unknown .…”

Acceptance & Commitment Therapy for ME/CFS (Chronic Fatigue Syndrome) – A feasibility study

“…Interestingly, since then, ME/CFS and stress-related exhaustion have been researched and clinically treated as two separate phenomena depending on their assumed etiologies (immunological vs. psychological stressors), despite the many similarities as discussed below (4,5). However, while attempting to differentiate the condition, the name Myalgic (muscle pain) Encephalomyelitis (inflammation of the brain and spinal cord) somewhat obscures the difficulties in finding a distinct marker, as the prevalence of muscle pain related to inflammation in the brain and the spinal cord in this condition is still in need of research support (6). Although numerous studies show abnormalities or differences in levels of immune and inflammatory markers in individuals diagnosed with ME/CFS compared to healthy controls, results are often unspecific and differences are only seen in some individuals (7).…”

“…Interestingly, biological sex moderated several associations, and future larger studies should include this aspect as inflammatory processes may differ in their relationships to symptom development between women and men in ME/CFS. Another aspect that could be considered both a limitation and a strength, is the measurement of (6). Furthermore, experimental studies show that the association between inflammation and subjective experience does not necessarily depend on the absolute level of inflammatory markers, making the significant vs non-significant associations between inflammatory markers in periphery and subjective symptom ratings in Study III more difficult to interpret (85).…”

<strong></strong>How Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) Progresses: A Framework for Research and the Prevention, Treatment, and Rehabilitation in ME/CFS

“…While there is no doubt that molecular research is essential to revealing disease pathways and for biomarker discovery, other types of research, such as clinical, epidemiological, environmental, health services, policy and education are essential for better disease recognition, prevention, diagnosis and treatment. Furthermore, we argue that researchers should consider the reproducibility of their studies, particularly when applying new technology, to avoid potential pitfalls such as those considered by VanElzakker et al (2019).…”