Our knowledge of the brain, the most complex organ, updates frequently. The long-held opinion that the brain is immunologically sealed off from the rest of the body was recently renewed by identifying lymphatic circulation in the brain. It also provided new insights into long-speculated chronic neuroinflammation in ME/CFS. However, previous detection methods limited the capability for effective integration of immunology and neurology. Blood tests are indirect and may have no relation to the brain because of the blood-brain barrier (a highly selectively permeable border regulating the passage of molecules into the brain). The collection of cerebrospinal fluid is highly invasive. Positron emission tomography (PET) requires injection of radioactive tracer. Moreover, the binding power of radioactive tracer varies across individuals. Here, we propose to throughout examine neuroinflammation in ME/CFS using the most advanced and only available recently MRI techniques.

Neuroinflammation is the activation of the brain's innate immune system, i.e., the activation of microglia (the brain’s first and main cells for the active immune defence) and astrocytes (cells maintaining the brain's stable environment). This study will extract the fingerprint of microglia and astrocyte activation by biologically modelling water diffusions in 384 scenarios. Furthermore, the brain lymphatic system in patients with ME/CFS will be quantified for the first time globally using advanced MRI. We will also investigate whole brain metabolites, temperature changes, and serum inflammation biomarkers.

In summary, this project is the world's first statistically powered and well-controlled study to test the neuroinflammation in ME/CFS. A robustly designed project will expand our understanding of ME/CFS by suggesting another research direction even if the hypothesis is rejected. The confirmed hypothesis will (a) elucidate the underlying disease process of ME/CFS and map brain microglia activation in ME/CFS; (b) enable the development of evidence-based treatments to control chronic neuroinflammation; (c) provide a potential mimic for animal models to further mechanism understanding and treatment development.

As a research participant, you would take part in:

• An online screening questionnaire.
• At your own pace, questionnaires for assess different aspects of mental and physical health status.
• Blood pressure, pulse rate, height, weight, and oxygen saturation measurements and a joint hypermobility task.
• One magnetic resonance imaging (MRI) scan (40 minutes’ scanning time plus preparation).
• One blood and saliva sample collection completed by a licensed phlebotomist at QML or Thompson Institute
• (Optional) Wearing an activity monitor wristwatch and chest strap to capture your physical activity, sleep/wake information and heart rate for fourteen days. The wristwatch and chest strap need to be returned after fourteen days of usage.

Participants with fatigue conditions will also take part in:

• Two clinical telehealth interviews with two specialists. Each interview will be scheduled for 30-45 minutes.

Note: If you have already participated in a previous CFS study with us, the physical assessment and clinical interviews will not need to be completed again.